The Role of Nod1 and Nod2 in the Pathogeneisis of Legionella Pneumophila Pneumoni

描述（由申请人提供）：本资助项目负责人为医学博士、博士，近期在西雅图华盛顿大学传染病科完成临床培训，致力于学术研究。该提案描述了一个为期5年的培训计划，旨在使PI成为宿主对呼吸道病原体保护的先天免疫领域的独立研究人员。具体而言，该提案的重点是细胞内核苷酸聚合结构域（NOD）样受体Nodi和Nod2在检测和保护嗜肺军团菌（Lp）肺炎中的作用，Lp是社区获得性肺炎的重要原因。在我们的初步研究中，我们已经证明Lp能够检测Lp，并且Nodi和Nod2缺乏的小鼠对Lp的免疫反应发生了改变。为了确定Nodi和Nod2在先天宿主对Lp免疫应答中的相关性，Aim 1提出了确定Nodi和Nod2缺乏导致全动物免疫应答受损的机制。在目的2中，我们将确定Nodi和Nod2对Lp反应的细胞机制。最后，在Aim 3中，我们计划通过分析Nodi和Nod2的人类遗传变异来确定人类意义，并在暴露于病原体后获得的Lp肺炎患者队列中确定与Lp肺炎的关联。完成这些目标将有助于更好地了解细胞内病原体检测在肺炎中的作用，可能导致对已知疾病个体的免疫治疗干预措施的发展或改进疫苗接种策略。提供给PI的资源和专业知识是唯一适合该项目的。主要导师托马斯·霍恩博士是先天免疫和人类遗传学领域的专家。Shawn Skerrett博士在Lp肺炎小鼠敲除模型方面有着丰富的经验。这种组合非常适合于理解对呼吸道病原体的先天免疫反应。该建议旨在通过增加我们对肺部病原体的宿主免疫反应的了解来改善公共卫生，以便有一天帮助设计有益的干预措施来改善结果。

DESCRIPTION (provided by applicant): The PI of this grant is an M.D., Ph.D. who is committed to academic research and recently completed his clinical training in the Division of Infectious Disease at the University of Washington in Seattle. The proposal describes a 5 year training program designed to establish the PI as an independent researcher in the field of innate immunity in the host protection to respiratory pathogens. Specifically, the proposal is focused on the role of intracellular Nucleotide Oligermerization Domain (NOD)-like receptors, Nodi and Nod2, in the detection of and protection from Legionella pneumophila (Lp) pneumonia, an important cause of community acquired pneumonia. In our preliminary studies we have shown that Lp is able to detect Lp, and that mice deficient in Nodi and Nod2 have altered immune responses to Lp. In order to determine the relevance of Nodi and Nod2 in the innate host immune response to Lp, Aim 1 proposes to determine the mechanisms by which Nodi and Nod2 deficiency lead to impaired inmiune responses in the whole animal. In Aim 2, we willdetermine the cellular mechanism of the Nodi and Nod2 response to Lp. Lastly, in Aim 3 we plan to define human significance by analyzing human genetic variability in Nodi and Nod2 and identify association to Lp pneumonia in a cohort of patients acquired Lp pneumonia following exposure to the pathogen. Completion of these aims will allow for better unstanding of the role of intracellular pathogen detection in pulmonary pneumonias possibly leading to development of immunotherapeutic interventions to individuals with known disease or improved vaccination strategies. The resources and expertise made available to the PI is uniquely suited for the project. Dr Thomas Hawn, the primary mentor, is an expert in the fields of innate immunity and human genetics. Dr. Shawn Skerrett has extensive experience with mouse knockout models of Lp pneumonia. The combination is uniquely suited to understanding innate immune responses to respiratory pathogens. This proposal seeks to improve public health by increasing our knowledge of the host immune response to pulmonary pathogens to one day help design beneficial interventions to improve outcome. RELEVANCE: Legionella pneumophila is an important lung pathogen, known to cause pneumonia in a significant proportion of the population. This proposal seeks to identify the mechanism of the host repsonse to this Legionella. Understanding the host immune resposne to Lp may lead to improved patient management of active Lp pneumonia, or to improved vaccination strategies in the future.